Project Summary/Abstract Powerful new Adapative Optics imaging technoIogies which sense ocular aberrations with a wave- front sensor and corrects them with a deformable mirror wave-front compensator, like Adaptive Optics Scanning Laser Ophthalmoscopy (AOSLO) and AO-OCT, provide detailed anatomical, physiological and functional information at the cellular level in the human eye. Physical Sciences Inc. (PSI) has recently demonstrated a new approach, called adaptive optics line scanning ophthalmoscopy (AO-LSO). The clinical AO-LSO retinal imager, invented and developed at PSI, greatly simplifies AO optical design, eliminates high-speed scanning components, and reduces the clinical footprint compared to research AOSLOs, while preserving many of the advantages of (line-)confocal imaging for resolving retinal layers. Although the AOSLO and AO-LSO provide the ability to routinely image and count cone photoreceptors, at present, there are no direct approaches for in vivo imaging of retinal ganglion cells in the human eye, or counting cell bodies in the inner retina. Our goal in Phase I is to demonstrate an advanced new design of the AO-LSO imager, (including an AO-OCT channel), with a new, high-sensitivity camera technology and line-illumination methods for phase gradient imaging of the inner retina. The envisioned platform will be engineered as a compact clinical system for flexible cellular imaging applications in vivo. An AO-LSO prototype instrument will be modified with new line-camera technology in Phase I, and used to investigate new imaging modalities. If successful, this approach and associated imaging algorithms will be improved in Phase II and used to monitor disease progression/regression and characterize inner retinal remodeling in patients at Children's Hospital Boston. A clinical investigator will provide feedback in Phase I and will lead a Phase II clinical study to evaluate the new capabilities of the phase gradient imaging approach. Phase III commercial development will provide clinicians with enhanced adaptive optics imaging capabilities not available in current retinal imagers.